The Role of Gαq in Regulating NLRP3 Inflammasome Activation

Overview

Journal Inflamm Res

Specialties Allergy & Immunology
Pathology

Date 2024 Oct 25

PMID 39455437

Authors

Ruixue Kong

Lijun Peng

Honggang Bao

Lulu Sun

Yan Feng

Hua Li

Dashan Wang

Affiliations

Soon will be listed here.

Abstract

Background: G proteins are a class of important signal transducers in mammalians. G proteins can corpoarated with G proteincoupled receptors (GPCRs) and transmit signals from extracellular stimuli into intracellular response, which will regulate a series of biological functions. G-proteins are heterotrimeric proteins composed of Gα, Gβ, and Gγ subunits. Based on structural and functional similarity of their α-subunits, G proteins are typically grouped into four classes (Gi, Gs, Gq/11, and G12/13). The Gq/11 subfamily consists of Gq, G11, G14, and G15/16 proteins. Gαq is the α-subunit of Gq protein and encoded by GNAQ. Our previous studies revealed that Gαq play an important role in regulating T cell survival and T cell differentiation. Inflammasomes are multiprotein complexes that play a critical role in modulating innate inflammatory response. NLRP3 inflammasome is currently the most extensively studied inflammasome.

Methods: We found that Gαq suppressed NLRP3 inflammasome activation in macrophage, Gαq also suppressed NLRP3 inflammasome activation in a LPS-induced sepsis mouse model. Gαq can locate to mitochondria and Gαq was required for the maintenance of mitochondrial homeostasis. Gαq regulated NLRP3 inflammasome activation by modulating mitochondrial reactive oxygen species (mtROS).

Results: We found that Gαq suppressed NLRP3 inflammasome activation in macrophage, Gαq also suppressed NLRP3 inflammasome activation in a LPS-induced sepsis mouse model. Gαq can locate to mitochondria and Gαq was required for the maintenance of mitochondrial homeostasis. Gαq regulated NLRP3 inflammasome activation by modulating mitochondrial reactive oxygen species (mtROS).

Conclusion: Our results indicate that Gαq regulates NLRP3 inflammasome activation by modulating mitochondrial ROS production. Our research provides new mechanistic insight into the activation of NLRP3 inflammasome. As it has been proved that NLRP3 inflammasome plays an important role in the pathogenesis many diseases such as Alzheimer's disease, cancer, and inflammatory bowel disease, Gαq might become a novel drug target for these diseases in future.

Citing Articles

The association between systemic immune-inflammation index and the short-term functional outcome of patients with aneurysmal subarachnoid hemorrhage: a meta-analysis.

Ye F, Jin J, Dai J Neurosurg Rev. 2025; 48(1):272.

PMID: 40016496 DOI: 10.1007/s10143-025-03300-y.

References

Liccardo F, Luini A, Di Martino R . Endomembrane-Based Signaling by GPCRs and G-Proteins. Cells. 2022; 11(3). PMC: 8834376. DOI: 10.3390/cells11030528. View

Calebiro D, Koszegi Z, Lanoiselee Y, Miljus T, OBrien S . G protein-coupled receptor-G protein interactions: a single-molecule perspective. Physiol Rev. 2020; 101(3):857-906. DOI: 10.1152/physrev.00021.2020. View

Zalewska M, Siara M, Sajewicz W . G protein-coupled receptors: abnormalities in signal transmission, disease states and pharmacotherapy. Acta Pol Pharm. 2014; 71(2):229-43. View

Li J, Ge Y, Huang J, Stromgaard K, Zhang X, Xiong X . Heterotrimeric G Proteins as Therapeutic Targets in Drug Discovery. J Med Chem. 2019; 63(10):5013-5030. DOI: 10.1021/acs.jmedchem.9b01452. View

Afzal M . G proteins: binary switches in health and disease. Cent Eur J Immunol. 2021; 45(3):364-367. PMC: 7789995. DOI: 10.5114/ceji.2020.101271. View

Kostenis E, Pfeil E, Annala S . Heterotrimeric G proteins as therapeutic targets?. J Biol Chem. 2020; 295(16):5206-5215. PMC: 7170519. DOI: 10.1074/jbc.REV119.007061. View

Kamato D, Mitra P, Davis F, Osman N, Chaplin R, Cabot P . Ga proteins: molecular pharmacology and therapeutic potential. Cell Mol Life Sci. 2016; 74(8):1379-1390. PMC: 11107756. DOI: 10.1007/s00018-016-2405-9. View

Wang D, Zhang Y, He Y, Li Y, Lund F, Shi G . The deficiency of Gαq leads to enhanced T-cell survival. Immunol Cell Biol. 2014; 92(9):781-90. DOI: 10.1038/icb.2014.53. View

Wang D, Liu Y, Li Y, He Y, Zhang J, Shi G . Gq Regulates the Development of Rheumatoid Arthritis by Modulating Th1 Differentiation. Mediators Inflamm. 2017; 2017:4639081. PMC: 5288531. DOI: 10.1155/2017/4639081. View

10.

Liu Y, Wang D, Li F, Shi G . Gαq controls rheumatoid arthritis via regulation of Th17 differentiation. Immunol Cell Biol. 2015; 93(7):616-24. DOI: 10.1038/icb.2015.13. View

11.

Huang Y, Xu W, Zhou R . NLRP3 inflammasome activation and cell death. Cell Mol Immunol. 2021; 18(9):2114-2127. PMC: 8429580. DOI: 10.1038/s41423-021-00740-6. View

12.

Kelley N, Jeltema D, Duan Y, He Y . The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int J Mol Sci. 2019; 20(13). PMC: 6651423. DOI: 10.3390/ijms20133328. View

13.

Yang Y, Wang H, Kouadir M, Song H, Shi F . Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis. 2019; 10(2):128. PMC: 6372664. DOI: 10.1038/s41419-019-1413-8. View

14.

Kong R, Sun L, Li H, Wang D . The role of NLRP3 inflammasome in the pathogenesis of rheumatic disease. Autoimmunity. 2021; 55(1):1-7. DOI: 10.1080/08916934.2021.1995860. View

15.

Li Z, Guo J, Bi L . Role of the NLRP3 inflammasome in autoimmune diseases. Biomed Pharmacother. 2020; 130:110542. DOI: 10.1016/j.biopha.2020.110542. View

16.

Glukhova A, Draper-Joyce C, Sunahara R, Christopoulos A, Wootten D, Sexton P . Rules of Engagement: GPCRs and G Proteins. ACS Pharmacol Transl Sci. 2020; 1(2):73-83. PMC: 7089011. DOI: 10.1021/acsptsci.8b00026. View

17.

Ricart-Ortega M, Font J, Llebaria A . GPCR photopharmacology. Mol Cell Endocrinol. 2019; 488:36-51. DOI: 10.1016/j.mce.2019.03.003. View

18.

Zhang H, Nielsen A, Stromgaard K . Recent achievements in developing selective G inhibitors. Med Res Rev. 2019; 40(1):135-157. DOI: 10.1002/med.21598. View

19.

Blevins H, Xu Y, Biby S, Zhang S . The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases. Front Aging Neurosci. 2022; 14:879021. PMC: 9226403. DOI: 10.3389/fnagi.2022.879021. View

20.

Coll R, Schroder K, Pelegrin P . NLRP3 and pyroptosis blockers for treating inflammatory diseases. Trends Pharmacol Sci. 2022; 43(8):653-668. DOI: 10.1016/j.tips.2022.04.003. View